P1392: INTERIM ANALYSIS OF FIRST IN HUMAN PHASE I-II CLINICAL TRIAL OF EX-VIVO GENE THERAPY FOR HURLER SYNDROME: AN UPDATE AT 3 YEAR FOLLOW-UP
Authors: Francesca Tucci, Giulia Consiglieri, Chiara Filisetti, Maurizio De Pellegrin, Renata Mellone, Francesca Fumagalli, Silvia Darin, Marina Sarzana, Stefano Scarparo, Francesca Ciotti, Paolo Silvani, Cristina Baldoli, Silvia Pontesilli, Rossella Parini, Giancarlo la Marca, Fabio Ciceri, Luigi Naldini, Alessandro Aiuti, Bernhard Gentner, Maria Ester Bernardo
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Mucopolysaccharidosis type I Hurler (MPSIH) is a rare lysosomal storage disorder caused by a defect in the IDUA gene leading to glycosaminoglycans (GAGs) accumulation in multiple organs and tissues, particularly in the skeleton and central nervous system (CNS). Allogeneic hematopoietic stem cell transplantation +/- pre-/peri-transplant enzyme replacement therapy represents the standard treatment, but skeletal and neurocognitive manifestations still progress over time. Aims: Here we report an update of interim results of a first-in-human phase I/II clinical trial (NCT03488394) of 8 MPSIH pediatric patients treated with autologous hematopoietic stem and progenitor cells transduced ex vivo with an α-L-iduronidase (IDUA)-encoding lentiviral vector after a busulfan/fludarabine-based conditioning regimen at 3-year follow-up. Methods: Patients [6 M, 2 F; median age at treatment 22 months (range:14-34)] lacked a non-heterozygous-HLA-matched donor and displayed IQ/DQ>70. Efficacy endpoint was blood IDUA up to supraphysiologic levels at 1 year (primary) and 3 years post gene therapy (GT) (secondary). Clearance of GAGs in urine and cerebrospinal fluid (CSF), skeletal and motor development were assessed as secondary and exploratory endpoints. The skeletal outcome was investigated by analyzing clinical (growth and measures of thoracolumbar kyphosis), functional (Peabody motor scale and joint range of motion, ROM) and radiological parameters (X-rays and MRI for the hip and the spine). Hip dysplasia (HD) was evaluated in 14 hips (7 patients, one patient was excluded from the analysis for bilateral hip dislocation already present before GT). Results: The treatment was generally well tolerated in all patients. The 5 patients positive for anti-IDUA antibodies before GT cleared them within 3 months after GT and remained negative at the last follow-up. 7/8 patients evaluable at 3 years after HSPC-GT showed sustained engraftment of gene-corrected cells with a median VCN per genome of 1.17 (range: 0.13-3.85) in PBMC and persistently supraphysiologic blood IDUA activity (median 133.4 µmol/L/h; range: 38.9-151.6), above the 97.5th percentile of age-matched healthy children. Accordingly, urinary GAG excretion levels remain normal or near normal in the 7 evaluable patients at the same follow-up. CSF IDUA activity became detectable by month 3 post-GT in all subjects and remained stable over time while GAGs levels in the CSF markedly decreased up to 3 year follow-up in 6/8 evaluable subjects. Patients showed growth within the normal range of healthy children adjusted for age and gender and reduction or stability in clinical measures of both sitting and standing kyphosis were noted. Progressive motor skills acquisition was observed in all subjects and among the ROM examined, shoulder mobility achieved the best outcome. GT showed positive effect on hip dysplasia showing a progression only in 1/14 hips. An overall stability of the typical MPSIH features at spine MRI was observed at the latest follow-up. Summary/Conclusion: These data show extensive metabolic correction and initial clinical response after GT and a favorable safety profile, highlighting its therapeutic potential for MPSIH treatment. A longer follow-up is needed to draw definitive conclusions on the impact of GT on MPSIH manifestations in the long term. Keywords: Stem cell gene therapy, Gene therapy